The overall objectives of this proposal are to further examine the mechanism of formation of microvascular occlusions found in the lenticulostriate (LSA) territory and their contribution to cerebral ischemia following acute middle cerebral artery (MCA) occlusion and reperfusion. The hypotheses to be tested state i) that such occlusions result from the adherence of PMN leukocytes to endothelial receptors in the LSA microvasculature, platelet-associated fibrin formation, and/or thrombosis, and ii) that novel, well-characterized reagents which inhibit leukocyte adherence/activation, platelet-fibrin association, or coagulation will increase microvascular patency, decrease infarction volume, and improve neurological outcome. PMN leukocytes and fibrin found in the microcirculation following MCA occlusion and reperfusion in the primate acute focal ischemia model suggest a pathogenesis for the "no-reflow" phenomenon. Measures which reduce the extent of this phenomenon may reduce the region of focal cerebral ischemia and improve neurological recovery. Heretofore, this concept has not been directly testable. Strategies to alter post-focal ischemia/reperfusion (I/R) microvascular occlusion formation and the neurological consequences of these interventions will be developed in three stages: i) mechanisms underlying microvascular occlusion formation will be examined by immunohistochemical methods in MCA reperfusion experiments; ii) modulation/inhibition of microvascular occlusions will be evaluated with novel techniques in short- term experiments which achieve maximum vascular patency; and iii) the ability of approaches developed in i) and ii) to also decrease infarction volume and improve functional outcome will be assessed in long-term experiments in the primate model. Outcomes in i) and ii) will be quantitated by video-imaging microscopy of microvascular patency, occlusion, and integrity using proven tissue techniques and data acquisition methods. The relevance of post-I/R microvascular events to local cerebral blood flow disturbances will be confirmed by magnetic resonance imaging and neuropathology. In view of clinical studies demonstrating successful cerebral arterial recanalization, the approaches in this proposal may have significant consequences for future acute stroke patient management and outcome.